Neuropathic Pain
Pain is the most common symptom for which patients seek medical help, and can be classified as either acute or chronic. Acute pain is precipitated by immediate tissue injury (e.g., a burn or a cut), and is usually self-limited. This form of pain is a natural defense mechanism in response to immediate tissue injury, preventing further use of the injured body part, and withdrawal from the painful stimulus. It is amenable to traditional pain therapeutics, including non-steroidal anti-inflammatory drugs (NSAIDs) and opioids. In contrast, chronic pain is present for an extended period, e.g., for 3 or more months, persisting after an injury has resolved, and can lead to significant changes in a patient's life (e.g., functional ability and quality of life) (Foley, Pain, In: Cecil Textbook of Medicine, pp. 100-107, Bennett and Plum eds., 20th ed., 1996).
Chronic debilitating pain represents a significant medical dilemma. Pain can be classified as either “nociceptive” or “neuropathic”. “Nociceptive pain” results from activation of pain sensitive nerve fibers, either somatic or visceral. Nociceptive pain is generally a response to direct tissue damage. The term “neuropathic pain” refers to pain that is due to injury or disease of the central or peripheral nervous system. In contrast to the immediate pain caused by tissue injury, neuropathic pain can develop days or months after a traumatic injury. Furthermore, while pain caused by tissue injury is usually limited in duration to the period of tissue repair, neuropathic pain frequently is long lasting or chronic. Moreover, neuropathic pain can occur spontaneously or as a result of stimulation that normally is not painful. Neuropathic pain is common in the following conditions: postherpetic neuralgia, trigeminal neuralgia, AIDS-related neuropathy, causalgia, diabetic neuropathy, chronic low back pain, back and neck pain with neuropathic involvement, phantom limb pain, atypical facial pain and cancer neuropathy (Berger et al., 2004, J. Pain 5:143-149).
Unfortunately, neuropathic pain is often resistant to available drug therapies; a hallmark of neuropathic pain is its intractability. Typical non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, indomethecin, and ibuprofen do not relieve neuropathic pain. The neuropathic pain observed in animal models predictive of human clinical outcome does not respond to NSAIDs. Treatments for neuropathic pain include opioids, anti-epileptics, NMDA antagonists, topical Lidocaine, topical Capsaicin and tricyclic anti-depressants. Current therapies have limited efficacy and may have serious side effects such as abuse potential, cognitive changes, sedation, and nausea. Many patients suffering from neuropathic pain have limited tolerance of such side effects. Accordingly, there is a need for additional neuropathic pain therapies.
PPAR Gamma Signaling Pathway and Modulators Thereof
The peroxisome proliferator-activated receptors (PPARs: α β/δ and γ) are a subfamily of ligand-inducible nuclear hormone transcription factors with roles in a range of physiological processes and disease states. PPARγ is widely expressed, particularly in tissues important for insulin action such as adipose tissue, skeletal muscle and liver. In the treatment of diabetes, activation of PPARγ improves glycemic control by improving insulin sensitivity, via activation of genes involved in the control of glucose production, transport and utilization.
PPARα is localized in tissues of the heart, liver and muscle, where it plays an important role in lipid metabolism by controlling genes relating to cellular free fatty acid metabolism and cholesterol trafficking PPARα activation decreases serum triglycerides (TGs) and increases levels of serum high-density lipoprotein (HDL)-cholesterol. Hypertriglyceridemia and low serum HDL-cholesterol are characteristic of both diabetic dyslipidemia and insulin resistance syndrome.
PPARγ has been identified as a potential target for neuropathic pain therapeutics, but the mechanism of neuropathic pain treatment through modulation of PPARγ has not been elucidated and is not understood. The Inventor's previously published PCT Patent Application WO 2008/063842 teaches PPARγ agonists as therapeutic agents for treating neuropathic pain. Other publications suggest antagonism of PPARγ for neuropathic pain therapy. In Published PCT Patent Application WO2006085686, Remedy for Neurogenic Pain, Tanabe & Tsutomu, Tokyo Medical & Dental University state: “ . . . it is intended to provide a remedy for neurogenic pain which contains, as the active ingredient, a PPARgamma antagonist (such as 2-chloro-5-nitro-N-phenylbenzamide) . . . a medicinal composition for treating neurogenic pain which contains, as the active ingredient, a PPAR antagonist . . . ” Tanabe and Tsutomu demonstrate that GW9662, a PPARγ antagonist demonstrates activity in a neurogenic pain model. Accordingly it is not clear whether agonism or antagonism of PPARγ results in therapeutic effects on neuropathic pain.
Even among the PPARγ agonists specifically taught by Published PCT Patent Application WO 2008/063842 (Tesaglitazar, Muraglitazar, Peliglitazar, Farglitazar, Reglitazar, Naveglitazar, Oxeglitazar, Edaglitazone, Imiglitazar and Sipoglitazar), further animal model testing has revealed a diversity of results. For instance, neither of Muraglitazar or Tesaglitazar showed any statistically significant difference from a vehicle control in the Bennett neuropathic pain animal model described below. See FIG. 1 for results. Therefore, it is not predictable whether any particular agonist or antagonist will or will not therapeutically reduce neuropathic pain.
Published PCT Applications WO 97/24334 and WO 00/29383 to Noritsugu Yamasaki et al., and related U.S. Pat. Nos. 6,166,219, 6,352,985, 6,703,410 and EP Patent 0882718 B1 teach benzimidazole derivatives having hypoglycemic or PPARγ agonist activity. Each of these patents and patent applications is incorporated herein by reference. Yamasaki et al. teach PPARγ agonist benzimidazole derivatives of Formula I:
                wherein        R1 represents a hydrogen atom, an arylsulfonyl group, or a lower alkyl group; said lower alkyl group may be substituted by an aryl group or an aryl group substituted by one or two substituents selected from a halogen atom, a haloaryl group, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, a nitro group, an amino group, a cyano group, an aryl group, an aryl-lower alkyloxy group, an arylsulfonyl-lower alkyl group, an aryl-lower alkyl group, a haloaryl-lower alkyloxy group, an arylsulfonylamino group, an arylcarbonylamino group, an arylcarbonyl group, an arylalkenyl group, a cyanoaryl group, and a heterocyclic group, or by a heterocyclic group;        R2 represents a hydrogen atom, a lower cycloalkyl group, a hydroxyl group, a hydroxy-lower alkyl group, a lower alkoxy group, a mercapto group, a lower alkylthio group, an amino group, a lower alkylamino group, a carboxyl group, an aryl group, or a lower alkyl group; said lower alkyl group may be substituted by a halogen atom, a lower alkoxy group, a cyano group, a halocarbonyl group, an aryl group, or a heterocyclic group;        R25 represents an alkyl group having up to 8 carbon atoms, a lower cycloalkyl group, a halo-lower alkyl group, a tri-lower alkylsilyl-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkylthio-lower alkyl group, an aryl group, a heterocyclic group, an aryl-lower alkyl group, or a hydroxy-lower alkyl group; said aryl group may be substituted by a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a nitro group;        R26 represents a hydrogen atom or a lower alkyl group; provided that, when R25 and R26 are both lower alkyl groups, they may be bonded together to form a ring;        Y represents a carbonyl group or a lower alkylene group;        A represents a single bond, or a lower alkylene or alkenylene group;        R4′ represents a hydrocarbon group or a halogenated hydrocarbon group; and        n means an integer from 0 to 3;        wherein        the arylsulfonyl group is selected from a benzenesulfonyl group, a toluenesulfonyl group, and a naphthalenesulfonyl group;        the term “lower” indicates that the group has from 1 to 6 carbon atoms, unless otherwise specifically indicated;        the aryl group is selected from a phenyl group and a naphthyl group, which may optionally be substituted by one or more substituents selected from a halogen atom, a lower alkyl group, a cyano group, a nitro group and a trifluoromethyl group;        the halo-lower alkyl group is a linear or branched alkyl group having up to 8 carbon atoms, which is substituted with one or more halogen atoms;        the heterocyclic group is selected from a pyridyl group, a quinolyl group, an isoquiriolyl group, a thiazolyl group, a thiadiazolyl group, a benzofuranyl group, a dibenzofuranyl group, a thianaphthalenyl group, a 1H-1,2,3-triazolyl group, a 1,2,4-triazolyl group, a tetrazolyl group, a furyl group, a thienyl group, a pyrrolyl group, an imidazolyl group, a pyrimidinyl group, an indolyl group, a benzimidazolyl group, which groups may optionally be substituted by one or more substituents of halogen atoms and lower alkyl groups; and        the lower cycloalkyl group is a cycloalkyl group having from 3 to 7 carbon atoms        or a pharmaceutically acceptable salt thereof.Yamasaki et al. further teach PPARγ agonist benzimidazole derivatives of Formula II:        
                wherein:        R27 represents a hydrogen atom, a lower alkyl group, an arylsulfonyl group or an aryl-lower alkyl group; wherein the aromatic ring moiety in said aryl-lower alkyl group may be substituted by one or two substituents selected from a halogen atom, a lower alkyl group, a halo-lower alkyl group, a cyanoaryl group, an amino group, a lower alkoxy group, a nitro group, a cyano group, an aryl group, a haloaryl group, an arylsulfonyl-lower alkyl group, an arylsulfonylamino group, an aryl-lower alkyloxy group, an aryl-lower alkyl group, a heterocyclic group, an arylcarbonyl group, an arylcarbonylamino group, and an aryl-lower alkyloxy group substituted by one or two halogen atoms;        R28 represents a hydrogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy-lower alkyl group, a lower cycloalkyl group, an aryl group, an aryl-lower alkyl group, a lower alkylamino group, a lower alkoxy group, a lower alkylthio group, a hydroxyl group, a mercapto group, an amino group, or a carboxyl group;        R25 represents an alkyl group having up to 8 carbon atoms, a halo-lower alkyl group, a tri-lower alkylsilyl-lower alkyl group, a lower alkoxy-lower alkyl group, a lower alkylthio-lower alkyl group, an aryl group, a heterocyclic group, an aryl-lower alkyl group, or a hydroxy-lower alkyl group; said aryl group may be substituted by a halogen atom, a lower alkyl group, a halo-lower alkyl group, a lower alkoxy group, or a nitro group;        R26 represents a hydrogen atom or a lower alkyl group; provided that, when R25 and R26 are both lower alkyl groups, they may be bonded together to form a ring;        Y represents a carbonyl group or a lower alkylene group;        A represents a single bond, or a lower alkylene or alkenylene group; and        R29 represents a hydrogen atom or a lower alkyl group        or a pharmaceutically acceptable salt thereof.Yamasaki et al. further teach PPARγ agonist benzimidazole derivatives of Formula II, wherein all groups are as given above, except:        R27 represents an aryl lower alkyl group whose aryl moiety may be substituted by one or two substituents selected from the group consisting of a halogen atom, a lower alkyl group, a halo-lower alkyl group, a cyanoaryl group, an amino group, a lower alkoxy group, a nitro group, a cyano group, an aryl group, a haloaryl group, an arylsulfonyl-lower alkyl group, an arylsulfonylamino group, an aryl-lower alkyloxy group, an aryl-lower alkyl group, a heterocyclic group, an arylcarbonyl group, an arylcarbonylamino group, and an aryl-lower alkyloxy group substituted by one or two halogen atoms;        Y represents a carbonyl group; and        A represents a single bond.Yamasaki et al. further teach PPARγ agonist benzimidazole derivatives of Formula II, wherein all groups are as given above, except:        R27 represents an aryl lower alkyl group whose aryl moiety may be substituted by one or two substituents selected from a halogen atom or an aryl group;        R28 represents a lower alkyl group or a lower cycloalkyl group;        R25 represents an alkyl group having up to 8 carbon atoms or an aryl group;        Y represents a carbonyl group; and        A represents a single bond.All chemical groups recited herein are defined according to the disclosure of Yamasaki et al. in EP 0882718 B1.Particular PPARγ agonist benzimidazole derivatives taught by Yamasaki et al. include 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide, 6-benzenesulfonylcarbamoyl-1-(2-chlorobenzyl)-2-methylbenzimidazole, 1-(biphenyl-4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-methylbenzimidazole, 1-(biphenyl-4-ylmethyl)-6-(1-butanesulfonylcarbamoyl)-2-ethylbenzimidazole, 6-benzenesulfonylcarbamoyl-2-cyclopropyl-1-(2-fluorobenzyl)-benzimidazole, 6-benzenesulfonylcarbamoyl-1-(2,4-dichlorobenzyl)-2-methylbenzimidazole, 6-benzenesulfonylcarbamoyl-1-(2,4-difluorobenzyl)-2-methylbenzimidazole, 6-(1-butanesulfonylcarbamoyl)-1-[(3-fluorobiphenyl-4-yl)methyl]-2-methylbenzimidazole, 1-(2,4-dichlorobenzyl)-2-methyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole, 1-(4-biphenylmethyl)-2-ethyl-6-(1-pentanesulfonylcarbamoyl)benzimidazole, and pharmaceutically acceptable salts thereof.        
Yamasaki et al. also teach methods of making the above PPARγ agonist benzimidazole derivatives, formulating them into pharmaceutical compositions and administering them in doses from 0.1 to 100 mg/kg, one to four times a day.
The benzimidazole derivative 3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide completed a Phase I clinical trial for Astellas Pharma Inc., and was entered into a Phase II clinical trial for type 2 diabetes (see clinicaltrials.gov, trial identifier NCT00036192). “While [3-(2,4-dichlorobenzyl)-2-methyl-N-(pentylsulfonyl)-3H-benzimidazole-5-carboxamide] advanced to Phase II clinical trials, its development was recently discontinued when no advantage [for type 2 diabetes] was demonstrated in clinical trials,” Meinke, Peter T., et al., “Nuclear Hormone Receptor Modulators for the Treatment of Diabetes and Dyslipidemia”, Annual Reports in Medicinal Chemistry (2006) 141:99-126, p. 109.